Belzutifan plus lenvatinib for patients (pts) with advanced clear cell renal cell carcinoma (ccRCC) after progression on a PD-1/L1 and VEGF inhibitor: Preliminary results of arm B5 of the phase 1/2 KEYMAKER-U03B study.
Authors: Laurence Albiges, Katy Beckermann, Wilson H. Miller, Jeffrey C. Goh, Pablo Gajate, Carole A. Harris, Cristina Suárez, Avivit Peer, Se Hoon Park, Walter Michael Stadler, Andrew James Weickhardt, Guy Faust, Peter C.C. Fong, Tom Waddell, Balaji Venugopal, Lina Yin, Ding Wang, Rodolfo F. Perini, Thomas Powles
Journal: Journal of Clinical Oncology (2023)

4553 Background: The oral HIF-2α inhibitor belzutifan demonstrated antitumor activity with manageable safety as monotherapy in pts with heavily pretreated ccRCC and in combination with a VEGF-TKI in pts who previously received a PD-1/L1 inhibitor. KEYMAKER-U03B (NCT04626518) is phase 1/2, multicenter, multi-arm, open-label, adaptive umbrella study. We present preliminary results from arm B5 for belzutifan + lenvatinib. Methods: In all arms, adults with histologically confirmed ccRCC, KPS ≥70%, and disease progression on or after PD-1/L1 inhibitor and VEGF-TKI treatment (in sequence or in combination) were enrolled. In arm B5, pts received belzutifan 120 mg PO QD + lenvatinib 20 mg PO QD. The study comprised a safety lead-in phase to establish the recommended phase 2 dose (RP2D), followed by an efficacy phase. Primary end point for the safety lead-in phase was safety and tolerability to establish RP2D; co-primary end points of the efficacy phase were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include clinical benefit rate (CBR; CR + PR + SD ≥6 mo), DOR and PFS per RECIST v1.1 by BICR. Response will be presented in pts who had an opportunity to receive ≥2 postbaseline scans due to ongoing enrollment. PFS was evaluated in all enrolled pts and safety in all treated pts. End points will be evaluated in each arm separately; no comparisons will be made across arms. Results: As of September 29, 2022, 32 pts were enrolled and 30 received treatment. Median age was 60.5 y, 78% were male and 78% had intermediate/poor IMDC risk. 23 pts were on treatment at data cutoff date. Median follow up was 6.9 mo (range: 0.1-18.2). Safety of belzutifan 120 mg + lenvatinib 20 mg was manageable. Of 10 evaluable pts in the safety lead-in phase, only 1 experienced a dose-limiting toxicity (grade 1 dyspnea). Among pts who had opportunity for ≥2 postbaseline scans (n = 24), ORR was 50% (95% CI, 29-71; all PRs); CBR was 54% (95% CI, 33-74). Median DOR was not reached (NR; range: 1.4+ to 14.0+ mo); 74% of responders remained in response for ≥12 mo by KM estimation. For all enrolled pts, median PFS was 11.2 mo (95% CI, 4-NR); 6-mo rate was 55%. In the safety analysis, 28 pts (93%) experienced a treatment-related AE (TRAE), most commonly (≥40%) anemia (43%), fatigue (43%), and hypertension (43%). Grade 3-4 TRAEs occurred in 15 pts (50%); most commonly hypertension (27%) and anemia (17%). 1 pt experienced grade 2 hypoxia. No pt died due to a TRAE. Conclusions: Preliminary data from the belzutifan + lenvatinib combination exhibited promising antitumor activity in pts with ccRCC that progressed on PD-1/L1 inhibitors and VEGF-TKIs. Safety findings were consistent with individual profiles of each agent. The combination is being further evaluated in the phase 3 LITESPARK-011 study. Clinical trial information: NCT04626518 .